Basic Science Research in
Colon Cancer Liver Metastasis
The M.D. Anderson Cancer Center has a very active program
investigating molecular mechanisms of colon cancer metastasis to the liver. The process of
metastasis is a dynamic process which requires the appropriate molecular machinery to
allow a tumor cell to proliferate in the colon, establish its own blood supply, invade
into surrounding tissues, be released into the circulation, adhere to the blood vessels of
the liver, invade into the liver (invasion), proliferate, and acquire its own blood supply
(angiogenesis). This complex process requires that the tumor cell interact with the
microenvironment of the liver such that the tumor cell can utilize the growth factors and
blood vessels of the liver in order to grow.
Figure 1: Mechanism of tumor growth and metastasis
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Identification of the molecular mechanisms that lead to colon
cancer metastasis to the liver allows the development of rational therapeutic strategies.
We currently have active programs investigating angiogenesis, growth factors and growth
factor receptors, signal transduction pathways, and mechanisms that promote tumor cell
survival.
Figure 2: Molecular mechanism of tumor growth and metastasis
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Factors which regulate colon cancer angiogenesis and metastasis,
have been studied in depth at the M.D. Anderson Cancer Center. It has been established
that vascular endothelial growth factor (VEGF), the most potent angiogenic factor
identified to date, leads to metastasis of colon cancer, and is associated with aggressive
disease. Since VEGF is important for colon cancer to metastasize to the liver, we have
utilized various strategies to inhibit VEGF activity so as to diminish the growth of colon
cancer metastasis. Recent studies have demonstrated that blocking VEGF activity decreases
the number of colon cancer metastasis, the size of colon cancer metastasis, and the number
of blood vessels within that metastasis. Furthermore, prolonged anti-VEGF therapy may
actually lead to death of tumor blood vessels, as well as tumor cells. Ongoing studies are
investigating the mechanisms of tumor cell death secondary to anti-VEGF therapy. Other
anti-angiogenic strategies are outlined in the accompanying figure. These strategies
include down-regulating angiogenic factor expression, blocking the activity of angiogenic
factors by utilizing antibodies that neutralize the factor itself or its receptor,
inhibiting the enzyme activity of the angiogenic factor receptor, blocking invasion of
blood vessels into the surrounding tissues, and other inhibitors of endothelial cell
proliferation.
In order for a tumor cell to divide, it must possess the
appropriate growth factor receptors to be able to respond to growth factors released by
the liver. These growth factor receptors are not only involved in tumor cell division, but
also in tumor cell survival. An active research program investigating mechanisms of growth
factor receptor augmentation of tumor growth has established that epidermal growth factor
receptor, hepatocyte growth factor receptor, and insulin-like growth factor receptor, are
all important factors in regulating tumor cell proliferation and survival. Numerous
strategies have been utilized to inhibit activity of these receptors, including monoclonal
antibodies and enzymes that inhibit the activity of these receptors. Preliminary analysis
suggests that these strategies can slow the growth of these tumors. Further analysis will
be necessary to determine if survival of mice can be prolonged by these agents in an
experimental model of colon cancer metastasis.
Tumor cells frequently receive outside signals which are then
transmitted through the interior of the cell to the nucleus where genes are activated.
This process, signal transduction, is an active area of investigation. In colon cancers
that metastasize to the liver, we have found that specific enzymes (Src, MAP
kinase, and others) are associated with increases in tumor aggressiveness. Furthermore,
these signal transduction pathways activate genes that lead to angiogenesis, cell
survival, or proliferation. Therefore, these signal transduction molecules are very
important mediators in the formation of colon cancer metastasis.
For colon cancers to grow and metastasize it must first invade into
the local tissues and eventually gain access to the lymphatic or blood circulation. Even
after this initial invasion, tumor cells deposited in the liver must invade into the liver
tissues. This process of invasion is regulated by specific factors released by tumor
cells.. These enzymes degrade the surrounding tissues allowing invasion of the tumor mass.
Investigations into the mechanism of how these enzymes are regulated in cancer and normal
tissues have led to the development of agents that inhibit such enzymes. However, initial
clinical studies with these agents have been associated with unexpected side effects and
disappointing results. Therefore, continued research in the field of colon cancer invasion
may lead to optimal therapeutic benefit with less side effects.
Over the last five to ten years, it has become apparent that tumor
cells express factors which allow them to survive under adverse conditions. Typically,
when normal cells encounter stress or develop a genetic mutation, they activate certain
processes within the cell that lead to "programmed cell death". This process,
apoptosis, is a process that prevents cells with genetic mutations from dividing and
forming cancers. However, in cancer, the process of apoptosis is altered such that cells
with genetic mutations are allowed to survive and divide even though there are alterations
within the cell which normally would lead to cell death. Examining the genes which
regulate the process of apoptosis allows us to identify targets which may make tumor cells
more susceptible to chemotherapy, radiation therapy, or other anti-tumor therapies.
A thorough understanding of the mechanisms of colon cancer
metastasis to the liver has led to the development of clinical trials utilizing antibodies
to growth factor receptors, anti-angiogenic compounds, signal transduction inhibitors, and
agents that induce tumor cell apoptosis. Information on these clinical trials are
available on the M.D. Anderson website, and questions regarding these trials can be
answered by contacting Patient Information.
Figure 3: Potential therapeutic targets
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